1 The issue of generalisability Current study objectives 1. To - PDF document

State of the ART Computational models that predict response to HIV therapy may reduce virological failure Key features of HIV Well-resourced settings Resource-limited and therapy costs in resource-limited treatment settings settings Strategy Individualised Public health Antiretroviral drugs Approx. 25 from 6 classes Limited availability / Revell AD, Wang D, Alvarez-Uria G, Streinu-Cercel A, Ene L, Wensing AMJ, affordability Hamers RL, Morrow C, Wood R, Tempelman H, DeWolf F, Nelson M, Montaner JS, Diagnostic & monitoring CD4, viral loads, resistance CD4 Lane HC, Larder BA on behalf of the RDI study group tools testing (Viral load?) Detection of failure Early – using regular viral Later – using CD4 counts or loads clinical symptoms Abstract O234, 11th International Congress on Drug Therapy in HIV Infection, Salvage Individualised – using Standard protocol – 11-15 November 2012; Glasgow Scotland genotype genotypes unaffordable Expertise available High and multidisciplinary Mixed and thinly spread 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012; Glasgow Scotland Consequences of the public health A big ? strategy for resource-limited settings • Rapid roll-out of ART 1 • Short-term cost-savings = more patients on therapy 1 • Extended the lives of millions What can we do to maximise the long-term • Unnecessary treatment switching 2 effectiveness of ART in RLS? • Delayed detection of failure and deferred treatment switching 3 How do we get the best out of a limited range of • Increased accumulation of resistance mutations 2,4 drugs? • Loss of therapeutic options 5 • Increased morbidity/mortality 4 Could the individualization of salvage ART using computational models be beneficial? 1. World Health Organisation. Antiretroviral therapy for HIV infection in adolescents and adults: recommendations for a public health approach - 2010 revision. WHO; Geneva: 2010. 2. Sigaloff KCE, Hamers RL, Wallis CL, Kityo C, Siwale M, Ive P, et al. Unnecessary Antiretroviral Treatment Switches and Accumulation of HIV Resistance Mutations; Two Arguments for Viral Load Monitoring in Africa. J AcquirImmune Defic Syndr. 2011; 58(1):23-31. 3. Zhou J, Li P, Kumarasamy N, Boyd M, Chen Y, Sirisanthana T, et al. Deferred modification of antiretroviral regimen following documented treatment failure in Asia: results from the TREAT Asia HIV Observational Database (TAHOD). HIV medicine. 2010; 11(1):31-9. 4. KeiserO, Chi BH, GsponerT, Boulle A, Orrell C, Phiri S, et al. Outcomes of antiretroviral treatment in programmes with and without routine viral load monitoring in southern Africa. AIDS. 2011; 25(14):1761-1769. 5. Barth RE, Aitken SC, Tempelman H, Geelen SP, van Bussel E, Hoepelman AIM, et al. Accumulation of drug resistance and loss of therapeutic options precede commonly used criteria for treatment failure in HIV-1 subtype C infected patients. Antivir Ther 2012; 17:377-386 11th International Congress on Drug Therapy in HIV Infection, 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012; Glasgow Scotland 11-15 November 2012; Glasgow Scotland Predicting response using RDI models with and without genotype and GSS from computational models common rules systems • Models can predict the response to ART with approx. 80% accuracy: – Trained using data from many thousands of patients – Input variables including genotype, viral load, CD4 count and Model AUC Accuracy treatment history 1,2 RDI geno 0.88 82% • Models can predict response without a genotype with a circa 70-75% RDI no geno 0.86 78% accuracy 3,4 ANRS 0.72 66% REGA 0.68 63% • At least comparable to the predictive accuracy of genotyping with rules based interpretation (62-69%) 5 Stanford db 0.71 67% Stanford ms 0.72 68% • Models now freely available via online HIV Treatment Response Prediction System (HIV-TRePS) 1. Revell AD, Wang D, Boyd MA, et al. The development of an expert system to predict virological response to HIV therapy. AIDS 2011; 25 :1855-1863. 2. Zazzi M, Kaiser R, Sönnerborg A, et al. Prediction of response to antiretroviral therapy by human experts and by the EuResist data-driven expert system (the EVE study). HIV Med 2010; 12 (4):211-218 3. Revell AD, Wang D, Harrigan R, et al. Modelling response to HIV therapy without a genotype. J Antimicrob Chemother 2010; 65 (4):605-607 4. Prosperi MCF, Rosen-Zvi M, Altman A, et al. Antiretroviral therapy optimisation without genotype resistance testing. PLoS One 2010; 5 (10):e13753 5. Frentz et al. Comparison of HIV-1 Genotypic Resistance Test Interpretation Systems in Predicting Virological Outcomes Over Time. PLoS One . 2010; 5 (7): e11505 Larder BA et al . 49th ICAAC, 2009; H-894 11th International Congress on Drug Therapy in HIV Infection, 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012; Glasgow Scotland 11-15 November 2012; Glasgow Scotland 1

The issue of generalisability Current study objectives 1. To compare the accuracy of HIV-TRePS for Previous studies have shown that models are more accurate • patients from ‘familiar’ settings to those from for patients from ‘familiar’ settings (with data in the training set) ‘unfamiliar’ resource-limited settings (RLS) than from unfamiliar settings Our models are therefore evaluated not only during cross • 2. To investigate if the system could identify validation but with independent test sets and data from other alternative regimens for cases that failed in the settings clinic with a higher predicted probability of success and without additional cost 11th International Congress on Drug Therapy in HIV Infection, International Workshop on HIV and Hepatitis Drug Resistance 2011 - abstract 34 11-15 November 2012; Glasgow Scotland Methods 1: Methods 2: HIV-TRePS models Assessment of model accuracy • 10 random forest models • Cross-validation • Trained with data from 14,891 cases of ART change • Independent set of 800 cases from familiar settings following virological failure in well-resourced countries • Input variables: viral load and CD4 count prior to treatment Unfamiliar RLS test sets change, treatment history, drugs in the new regimen, time to • 231 cases from sub-Saharan Africa (5 countries) follow-up and follow-up viral load. • 375 cases from Romania • Output: prediction of the probability of response to ART (<400 copies HIV RNA/ml) • 206 cases from India • Main outcome measure: The area under the ROC curve (AUC) 11th International Congress on Drug Therapy in HIV Infection, 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012; Glasgow Scotland 11-15 November 2012; Glasgow Scotland Results 1: Results 2: ROC curves Accuracy: familiar vs unfamiliar settings DATA SET AUC Familiar RDI (n=800) 0·77 95%CI (0·73, 0·80) Unfamiliar from RLS Southern Africa (n=231) 0·60 ** 95%CI (0·52, 0·69) Romania (n=375) 0.71 95%CI (0.66, 0.76) India (n=206) 0.63 * 95%CI (0.55, 0.71) * p<0.01 vs RDI 800 **p<0.001 vs RDI 800 (de Long’s test) 11th International Congress on Drug Therapy in HIV Infection, 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012; Glasgow Scotland 11-15 November 2012; Glasgow Scotland 2